Strategy for Improving Stroke Treatment Response (SISTER) Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 300
- 试验地点
- 104
- 主要终点
- Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS)
研究概览
简要总结
SISTER is a Phase-II, prospective, randomized, placebo-controlled, blinded, dose finding trial that aims to determine the safety and preliminary efficacy of TS23, a monoclonal antibody against the alpha-2 antiplasmin (a2-AP), in acute ischemic stroke.
详细描述
SISTER is a Phase II, Bayesian, adaptive, randomized, dose-finding trial of TS23 in patients with acute ischemic stroke. Patients with an anterior cerebral circulation acute ischemic stroke and present between 4.5 to 24 hours of their last known well with a presenting NIH Stroke Scale Score >/=4 (with the patient having a clearly disabling deficit if the NIHSS is 4 or 5) and an imaging evidence of salvageable brain tissue will be eligible and will be approached for an informed consent for study participation. After informed consent is provided, the study will randomize to 4 doses of TS23 and placebo. The trial will enroll up to 300 subjects at up to 60 participating US sites and up to 17 Canadian sites.
The effects of TS23 will be evaluated on two following primary outcomes using a utility function: 1) primary safety outcome: any intracerebral hemorrhage at 30 (+/-4) hours and 2) primary efficacy outcome: NIH Stroke Scale score at 30 (+/-4) hours after drug administration. The study will follow participants for 90 (+/-7) days.
Primary Objective: To identify a dose of TS23 that is safe and more efficacious than placebo for the treatment of patients from 4.5 to 24 hours of last known well, who have evidence of core-penumbra mismatch on perfusion imaging and are not a candidate for standard of care reperfusion therapies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 years and older
- •Suspected anterior circulation acute ischemic stroke
- •NIH Stroke Scale score ≥4 prior to randomization
- •a. The participant must have a clearly disabling deficit if NIHSS is 4-
- •Favorable baseline neuroimaging consisting of all of the following:
- •ASPECTS of 6 or more on CT (or ASPECTS of ≥7 on MRI)
- •Favorable perfusion imaging on CT perfusion (CTP)/MR-perfusion weighted imaging (PWI) consisting of all of the following:
- •i. Mismatch ratio of penumbra: core >1.2 ii. Mismatch volume >10 cc iii. Core <70 cc
- •c. If CT hypodensity is present, then in the investigator's visual assessment, the total acute infarct volume combined area of (a) the CT hypodensity and (b) the perfusion-based core volume (CBF<30%) should be smaller than perfusion-based volume (area of Tmax>6s minus CBF<30%).
- •Able to receive assigned study drug within 4.5 to 24 hours of stroke onset or last known well.
- •Able to receive assigned study drug within 120 minutes of qualifying perfusion imaging. *
- •Informed consent for the study participation obtained from participant or their legally authorized representatives.
- •Study drug administration is encouraged within 90 minutes after qualifying perfusion image but is allowed up to 120 minutes. After 120 minutes, another perfusion image to ensure that inclusion criteria are met is required.
排除标准
- •Received endovascular treatment with clot engagement.
- •Patients who undergo groin puncture but clot engagement is not attempted due to spontaneous distal migration are permitted to be enrolled in the trial if all other eligibility criteria are met.
- •Patients who undergo groin puncture but clot is not engaged due to reasons other than spontaneous distal migration are NOT permitted.
- •Received or planned to receive intravenous thrombolysis.
- •Pre-stroke modified Rankin score >
- •Previous treatment with TS23 or known previous allergy to antibody therapy.
- •Known pregnancy, women who are breastfeeding or plan to breastfeed within 3 months of receiving TS23 or have a positive urine or serum pregnancy test for women of childbearing potential.
- •Known previous stroke in the past 90 days.
- •Known previous intracranial hemorrhage, intracranial neoplasm, subarachnoid hemorrhage, or arterial venous malformation.
- •Known active diagnosis of intracranial neoplasm.
- •Clinical presentation suggestive of a subarachnoid hemorrhage, even if initial CT scan was normal.
- •Surgery or biopsy of parenchymal organ in the past 30 days.
- •Known trauma with internal injuries or persistent ulcerative wounds in the past 30 days.
- •Severe head trauma in the past 90 days.
- •Persistent systolic blood pressure >180mmHg or diastolic blood pressure >105mmHg despite best medical management.
- •Serious systemic hemorrhage in the past 30 days.
- •Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with International Normalized Ratio (INR) >1.
- •Platelets <100,000/mm
- •Hematocrit <25 %.
- •Elevated aPTT above laboratory upper limit of normal.
- •Creatinine > 4 mg/dl, or patients receiving renal dialysis, regardless of creatinine.
- •Received the following within the previous 24 hours:
- •If patient received unfractionated heparin within the last 24 hours, the patient must have an aPTT within normal range prior to enrollment.
- •Low molecular weight heparins such as Dalteparin, enoxaparin, tinzaparin in full dose within the previous 24 hours.
- •Received Factor Xa inhibitors (such as Fondaparinux, apixaban or rivaroxaban) within the past 48 hours.
- •Received direct thrombin inhibitors (e.g., argatroban, dabigatran, bivalirudin, desirudin, lepirudin) within 48 hours.
- •Received glycoprotein IIb/IIIa inhibitors within the past 14 days.
- •Known pre-existing neurological or psychiatric disease which would confound the neurological/functional evaluations.
- •Current participation in another research drug treatment protocol (i.e., participants could not start another experimental agent until after 90 days).
- •Concurrent acute myocardial infarction, pulmonary embolism, deep venous thrombosis or other thrombotic event that requires anticoagulation or anti-platelet treatment.
研究组 & 干预措施
Placebo
Placebo
干预措施: TS23 (Biological)
Dose 1 TS23
low dose
干预措施: TS23 (Biological)
Dose 2 TS23
next higher dose
干预措施: TS23 (Biological)
Dose 3 TS23
next higher dose
干预措施: TS23 (Biological)
Dose 4 TS23
highest dose
干预措施: TS23 (Biological)
结局指标
主要结局
Stroke severity as measured by the National Institutes of Health Stroke Scale (NIHSS)
时间窗: At 30 (+/- 4) hours after study drug
NIHSS is a stroke severity score that ranges from 0 to 42, with higher numbers indicating a more severe stroke. The NIHSS will be adjusted for the baseline value in analysis.
The proportion of patients with ANY intracerebral hemorrhage (ICH)
时间窗: At 30 (+/- 4) hours after study drug
Any ICH visualized on the follow-up CT scan
次要结局
- Proportion of patients with non-intracerebral hemorrhage major or clinically relevant non-major bleeding(30 days of study drug administration.)
- Plasma fibrinogen level(3 (±1) h after completion of study drug)
- Proportion of patients with non-bleeding severe adverse events(90 (±7) days)
- Proportion of patients with stroke-related and all-cause deaths(90 (±7) days)
- Frequency of Modified Rankin (mRS) score of 0-1 or returning to pre-stroke mRS.(Proportion of patients with modified Rankin scale score 0-1 or return to pre-stroke mRS at 90 (+/-7) days.)
- NIHSS(72 (±12) hours (or at discharge if sooner) after study drug administration.)
- α2-antiplasmin (a2AP) level in plasma(at 3 (±1) h after completion of study drug administration)
- Matrix metalloproteinase-9 level in plasma(3 (±1) h after completion of study drug)
- % brain tissue reperfusion(30 (±4) h after study drug administration)
- Evaluation of anti-drug antibodies(will be measured at baseline and 90 (±7) days follow-up visit for approximately 50 mITT participants.)
- Improvement in level of global disability measured by modified Rankin Score (mRS distribution)(90 (±7) days)
- Proportion of patients with symptomatic intracerebral hemorrhage(30 (±4) h of study drug administration)
- Plasma fibrinogen level(3 (±1) h after completion of study drug)
- Improvement in level of global disability measured by modified Rankin Score (mRS distribution)(90 (±7) days)
- Frequency of Modified Rankin (mRS) score of 0-1 or returning to pre-stroke mRS.(Proportion of patients with modified Rankin scale score 0-1 or return to pre-stroke mRS at 90 (+/-7) days.)
- NIHSS(72 (±12) hours (or at discharge if sooner) after study drug administration.)
- α2-antiplasmin (a2AP) level in plasma(at 3 (±1) h after completion of study drug administration)
- Matrix metalloproteinase-9 level in plasma(3 (±1) h after completion of study drug)
- % brain tissue reperfusion(30 (±4) h after study drug administration)
- Pharmacokinetic analyses(3 (±1) h, 30 (±4) h, 30 (±5) days & 90 (±7) days after study drug administration. At 90 (±7) days for approximately 50 mITT participants. After approximately 50 mITT participants, it will be obtained at 72h(+12 hrs)/discharge visit, whichever comes 1st.)
- Evaluation of anti-drug antibodies(will be measured at baseline and 90 (±7) days follow-up visit for approximately 50 mITT participants.)
- Proportion of patients with symptomatic intracerebral hemorrhage(30 (±4) h of study drug administration)
- Proportion of patients with non-intracerebral hemorrhage major or clinically relevant non-major bleeding(30 days of study drug administration.)
- Proportion of patients with non-bleeding severe adverse events(90 (±7) days)
- Proportion of patients with stroke-related and all-cause deaths(90 (±7) days)